During the course of this first funding cycle, Project 2 made several important discoveries. Among these were the following: (1) Multiple signaling kinases are persistently activated by pro-oxidant insults in vitro and cerebral ischemia in vivo. (2) Pro-oxidant insults cause persistent reductions in at least three protein phosphatases. (3) Persistent activation of these signaling kinases converts them into death-inducing kinases that contribute to oxidative damage, AD-like neuropathology and neuronal cell death. (4) Both feminizing and non-feminizing estrogens prevent the pro-oxidant induced persistent down regulation of protein phosphatases and the persistent activation of signaling kinases. Also, estrogens ameliorate neuronal death and AD neuropathology causes by persistent kinase activation. (5) Cerebral ischemia causes phosphatase decline, persistent kinase activation, progressive AD neuropathology, hippocampal damage and cognitive decline in young rats. (6) Persistent inhibition of protein phosphatases causes cognitive decline and tauopathy in young rats. Having demonstrated these normally functioning signaling pathways become, with persistent activation, death-inducing kinase pathways, we propose to determine the causative factors by (Aim 1) determining the mechanism by which chronic phosphatase inhibition causes cognitive and LTP decline and AD neuropathology; (Aim 2) determining the role of persistent kinase activation in AD neuropathology; (Aim 3) determining the role of induction of cyclin-dependent kinases in AD neuropathology; and determining the effects of E2 and non-feminizing estrogens on insult-induced AD-like neuropathology; (Aim 4) determining the mechanism by which estrogens ameliorate these changes; and ( Aim 5) determining the role of L-type Ca2+ channels in the estrogen up regulation of protein phosphatases. Collectively, these studies will determine the mechanism(s) by which oxidative events initiate and contribute to the progression of AD neuropathology and the extent to which estrogen can antagonize these effects of oxidative stress.